Angiogenesis is the formation of capillaries from preexisting vessels, generally occurring in the embryo and adult mammalian organisms as part of normal growth and repair, such as wound healing. However, uncontrolled angiogenesis is also associated with cellular proliferative disorders such as cancer, diabetic retinopathy, macular degeneration, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma, and haemangioma. Solid tumor growth and invasion depend upon an adequate blood supply to provide cellular growth factors, nutrients, and to remove metabolic by-products from active cell division.
Tumor angiogenesis involves a number of sequential and complex processes beginning with the production and release of angiogenic factors by tumor cells or their surrounding matrix, culminating in development of the tumor vasculature. This multistep cascade includes endothelial cell (EC) activation, proliferation, and migration, followed by tube formation and maturation. Angiogenic growth factors, such as basic fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF), which are expressed during growth of the tumor, are key modulators of EC function and the entire neovascular process. Accordingly, small molecular weight compounds that are specific and selective inhibitors of FGF and VEGF receptor tyrosine kinases on ECs are useful as antiangiogenic therapies for treating cancer and other diseases caused by uncontrolled cellular proliferation.
U.S. Pat. No. 5,733,914, incorporated herein by reference, describes a broad class of pyrido[2,3-d]pyrimidines that are said to be useful to treat cancer and other cellular proliferative diseases due to their ability to inhibit a wide variety of growth factor receptor tyrosine kinases such as platelet derived growth factor PDGF), epidermal growth factor (EGF), as well as VEGF and FGF. The compounds are substituted at the 6-position by aryl and heteroaryl groups, which groups may be substituted with various moieties including halo, alkyl, alkoxy, thio, thioalkyl, hydroxy, amino, and alkanoyl. The disclosure points to dihalophenyl as a preferred substituent on the pyrido[2,3-d]pyrimidine nucleus, and specifically the 2,6-dichlorophenyl as being the most preferred. The patent additionally describes a variety of possible substituent groups at the 2-position of the pyrido[2,3-d]pyrimidine nucleus, including arylamino, with phenylamino said to be the most preferred. These compounds suffer from lack of bioavailability, metabolic stability, and enzyme selectivity.
We have now discovered a series of pyrido[2,3-d]pyrimidines that are surprisingly more potent and selective as inhibitors of VEGF and FGF than the compounds described in U.S. Pat. No. 5,733,914, and which are bioavailable and stable in mammals. The present compounds are characterized as 2-[(4-pyridyl)amino]-6-(3,5-dialkoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-ones. An object of this invention is to provide potent, selective, and metabolically stable inhibitors of VEGF and FGF, and a method of treating diseases resulting from uncontrolled cellular proliferation using such compounds.